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Letters to the Editors Letters to the Editors Atypical phenotype without symptoms, genetic analyses for MEFV, suggested that the manifestations of FMF fever in a Japanese family MVK, TNFRSF1A, NLRP3, PSTPIP1, are primarily attributed to the difference NLRP12, TNFAIP3, IL1RN, IL36RN and in the mutational pattern in MEFV (5-7). with an autosomal dominant CARD14 were performed in the proband Thr577 amino acid exists in the coiled-coil transmission of familial using targeted next-generation sequencing, domain, followed by the B30.2 domain of Mediterranean fever due to revealing homozygous E148Q, heterozy- pyrin; mutations at this amino acid residue heterozygous MEFV gous L110P variant and T577N mutation are extremely rare (8). Recently, all mem- Thr577Asn mutations in MEFV. In addition, MEFV was analysed bers with both homozygous Glu148Gln in all family members using targeted next- (E148Q) and heterozygous MEFV T577N generation sequencing, further confirming mutations/variants in a Japanese family Sirs, the detected mutations using direct se- were reported to inherit autoinflammatory Familial Mediterranean fever (FMF) is an quencing. All family members with hete- disorders characterised by recurrent chest inherited autoinflammatory disease caused rozygous MEFV T577N mutations demon- pain without fever (3). However, it remains by mutations in the Mediterranean fever strated recurrent chest pain and/or arthritis unclear which mutation/variant of T577N (MEFV) gene. Although FMF is classi- without fever, whereas his daughter, who or E148Q contributes to these inheritable cally transmitted by autosomal recessive had the heterozygous MEFV Glu148Gln and clinical characteristics. In our cases, all transmission, rare cases of dominant trans- (E148Q) variant, only exhibited recurrent family members with heterozygous MEFV mission have been reported (1-3). Herein, abdominal pain and arthritis with high fe- T577N mutations experienced recurrent we report a rare case of a Japanese family ver (Fig. 1 A-B). All family members with chest pain and/or arthritis without fever with an autosomal dominant transmission clinical symptoms showed good response (Table I). While only one family mem- of FMF due to heterozygous Thr577Asn to colchicine and were finally diagnosed ber with only heterozygous MEFV exon 2 (T577N) mutations in the exon 8 of MEFV. with FMF. Both the proband and his daugh- variants experienced recurrent abdominal A 55-year-old Japanese man had been ex- ter were diagnosed with Henoch-Schönlein pain and high fever, these symptoms were periencing recurrent attacks of chest pain purpura (HSP) in their childhood. In addi- completely different from those of other and arthritis without fever lasting for 3–4 tion, both the proband and his mother had family members with heterozygous MEFV days since 15 years of age. His laboratory a history of non-bacterial osteomyelitis in T577N mutations. These findings suggest findings showed high C-reactive protein their wrists. different clinical characteristics and ge- and serum amyloid A levels during these at- Although the genetic characteristics of pa- netic penetrance between MEFV mutation/ tacks, leading to a suspicion of FMF. After tients with FMF in Japan include a lower variant of T577N and exon 2. Thus, MEFV treatment with 1.0-mg/day colchicine, no percentage of MEFV exon 10 mutations T577N mutations may contribute to atypi- further attacks were observed. He was fi- with a high penetrance and percentage cal phenotype presenting without fever and nally diagnosed with FMF according to the of MEFV exon 2 mutations and low pen- may cause autosomal dominant transmis- Tel Hashomer criteria (4). Because his fam- etrance than those of patients with FMF sion due to extremely high penetrance. In ily members had similar, common recurrent in Western countries (5), previous reports addition, although some reports have dem- Fig. 1. A: Direct sequencing of MEFV exon 8. Red arrow indicates heterozygous MEFV T577N mutations among some members of the Japanese family. B: Pedigree of the Japanese family. Squares and circles indicate male and female family members, respectively. Diagonal lines indicate deceased individuals. Black arrow indi- cates the proband. MEFV generic analyses were performed in all members indicated using asterisks, and mutations with amino acid substitution detected using genetic analyses are shown below squares or circles. Aforementioned shapes filled with black colour represent members with recurrent clinical symptoms and the details and onset age of these symptoms are also shown below the shapes. Clinical and Experimental Rheumatology 2019 S-161 Letters to the Editors Table I. Characteristics of typical FMF cases, previous reports with heterozygous MEFV T577N mutations and present case. Characteristics Typical FMF Previous reports Present cases Stoffels Nakaseko Proband Mother Sister Eldest Third Eldest son Fourth et al. (1) et al. (3) daughter daughter daughter Types of MEFV Great variety Heterozygous Homozygous Heterozygous Homozygous Heterozygous Heterozygous Heterozygous Heterozygous Heterozygous mutations/variants T577N E148Q L110P E148Q E148Q E148Q E148Q E148Q E148Q Heterozygous Homozygous Heterozygous Heterozygous Heterozygous Heterozygous Heterozygous T577N E148Q T577N P369S T577N T577N T 5 7 7 N Heterozygous Heterozygous T577N R408Q Heterozygous T577N Inheritance Autosomal Autosomal Autosomal Autosomal dominant recessive dominant dominant probable Age at onset (years) Superiority of 6, 10 3, 5, 16 10 10 14 5 11 16 7 young-onset Fever ++ ++ − − − − − + − − Chest pain + ++ ++ ++ ++ ++ ++ − ++ − Abdominal pain ++ ++ ± − − − − + − − Arthralgia + ++ − ++ ++ ++ ++ + − + Skin lesions + + − − − − − − − − Duration of the attacks 1–3 days Days to weeks Days to months 3–4 days 1–2 days 1–2 days 3–4 days 3–4 days 2–3 days 2–3 days Good response to ++ ++ ++ ++ ++ ++ ++ ++ ++ ++ colchicine History of HSP ± NA NA + − − + − − − FMF: familial Mediterranean fever; MEFV: Mediterranean fever; HSP: Henoch-Schönlein purpura; NA: not available onstrated a comparatively high prevalence Please address correspondence to: fever. Arthritis Rheum 1997; 40: 1879-85. of MEFV mutations among patients with Dr Tomohiro Koga, 5. ENDO Y, KOGA T, ISHIDA M et al.: Musculo- skeletal manifestations occur predominantly in pa- HSP (9) and non-bacterial osteomyelitis as Department of Immunology and Rheumatology, Unit of Advanced Preventive Medical Sciences, tients with later-onset familial Mediterranean fever: a complication of FMF (10), high frequen- Graduate School of Biomedical Sciences, Data from a multicenter, prospective national cohort cies of previous HSP and non-bacterial os- Nagasaki University, 1-7-1 Sakamoto, study in Japan. Arthritis Res Ther 2018; 20: 257. teomyelitis were noted in our cases and Nagasaki 852-8501, Japan. 6. SAMUELS J, AKSENTIJEVICH I, TOROSYAN Y may be caused by MEFV T577N mutations. E-mail:[email protected] et al.: Familial Mediterranean fever at the millen- nium. Clinical spectrum, ancient mutations, and a Competing interests: none declared. When some members in family have recur- survey of 100 American referrals to the National rent FMF-related symptoms, even without © Copyright CLINICAL AND Institutes of Health. Medicine (Baltimore) 1998; 77: fever, the existence of MEFV T577N muta- EXPERIMENTAL RHEUMATOLOGY 2019. 268-97. tions should be considered and MEFV ge- 7. MOGHADDAS F, LLAMAS R, DE NARDO D et al.: netic analyses should be performed. References A novel Pyrin-Associated Autoinflammation with 1. STOFFELS M, SZPERL A, SIMON A et al.: Neutrophilic Dermatosis mutation further defines 14-3-3 binding of pyrin and distinction to Familial 1 MEFV mutations affecting pyrin amino acid 577 Y. ENDO , MD cause autosomal dominant autoinflammatory dis- Mediterranean Fever. Ann Rheum Dis 2017; 76: 1 T. KOGA , MD, PhD ease. Ann Rheum Dis 2014; 73: 455-61. 2085-94. 2 M. NAKASHIMA , MD, PhD 2. ROWCZENIO DM, IANCU DS, TROJER H et al.: 8. YAMAGUCHI-KABATA Y, NARIAI N, KAWAI Y et H. MISHIMA3, DDS, PhD Autosomal dominant familial Mediterranean fever al.: iJGVD: an integrative Japanese genome varia- K. YOSHIURA3, MD, PhD in Northern European Caucasians associated with tion database based on whole-genome sequencing. A. KAWAKAMI1, MD, PhD deletion of p.M694 residue-a case series and genetic Hum Genome Var 2015; 2: 15050. exploration. Rheumatology (Oxford) 2017; 56: 209- 9. GERSHONI-BARUCH R, BROZA Y, BRIK R: 1 Department of Immunology and Rheumatology, 13. Prevalence and significance of mutations in the fa- Unit of Advanced Preventive Medical Sciences, 3. NAKASEKO H, IWATA N, IZAWA K et al.: Expand- milial Mediterranean fever gene in Henoch-Schön- Nagasaki University Graduate School of ing clinical spectrum of autosomal dominant pyrin- lein purpura. J Pediatr 2003; 143: 658-61. 2 Biomedical Sciences, Nagasaki; Centre for associated autoinflammatory disorder caused by the 10. GEZGIN YILDIRIM D, BEDIR DEMIRAG T, Rheumatic Diseases, Kurume University heterozygous MEFV p.Thr577Asn variant. Rheu- AKDULUM I, YILMAZ G, BAKKALOGLU S: Medical Centre, Kurume; 3Department of matology (Oxford) 2019;58:182-4. Chronic non-bacterial osteomyelitis coexistent with Human Genetics, Nagasaki University Atomic 4. LIVNEH A, LANGEVITZ P, ZEMER D et al.: familial Mediterranean fever. Clin Exp Rheumatol Bomb Disease Institute, Nagasaki, Japan. Criteria for the diagnosis of familial Mediterranean 2018; 36 (Suppl. 115): S150. S-162 Clinical and Experimental Rheumatology 2019.
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